Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy. This disease frequently metastasizes to bone marrow (most likely), liver and other organs. Precise staging of the disease is essential to ensure the most appropriate treatment plan. The current battery of imaging tests for staging and re- staging combines separately acquired 99mTc-methylene diphosphonate (99mTc-MDP) scintigraphy, 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy, and computed tomography (CT) imaging. Planar scintigraphy images, which cannot be anatomically co-registered to CT, have low spatial resolution and do not provide precise anatomic localization, resulting in lower sensitivity for lesion detection as compared to tomographic imaging techniques. Although not as frequent as scintigraphy imaging, separately acquired 99mTc-MDP and 123I-MIBG SPECT are also used to image neuroblastoma patients. Filtered back-projection (FBP) is the standard reconstruction algorithm used in clinic to reconstruct the SPECT images. More advanced iterative reconstruction algorithms, such as Siemens Flash3D, are becoming available in clinic but remain very expensive. Although current clinical approaches offer high sensitivity and specificity for imaging neuroblastoma, it is desirable to reduce the number of scans for each staging and re-staging because most of the children typically require sedation or general anesthesia during imaging. More importantly, it is very desirable to further reduce dose for these young patients while preserving the same image quality. We propose imaging these patients using simultaneous 99mTc-MDP/123I-MIBG SPECT in addition to a non- contrast-enhanced low-dose CT on a SPECT-CT scanner. Our approach will require much less dose without comprising image quality and avoid repositioning of the patient and multiple sedations/anesthesias. A low-variance joint ordered-subset expectation maximization (LV-JOSEM) reconstruction algorithm will be developed. The algorithm will be validated by Monte Carlo simulation and phantom studies. The dual-isotope patient studies will be compared to the sequential single-isotope studies on the basis of performance of lesion detection task in detecting the presence of a lesion of known size, shape, and contrast on an anatomic background. We will estimate how much dose can be reduced using dual-radionuclide imaging with LV-JOSEM to achieve the same lesion detectability as that using the standard clinical approaches. PUBLIC HEALTH RELEVANCE: Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy. The aim of this project is to demonstrate that simultaneous 99mTc-MDP/123I-MIBG SPECT imaging with a low-variance joint ordered-subset expectation maximization (LV-JOSEM) reconstruction algorithm would require much less dose than sequential single-isotope approaches, avoiding repositioning the patient between scans, and eliminating the need for multiple sedations and general anesthesia for imaging of neuroblastoma.